Emerging Concepts of Pathogenesis and Comprehensive Therapeutic Strategies for Spinocerebellar Ataxia Type 3

S. Roy, Xiaolei Liu
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Abstract

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the ATXN3 gene, situated at 14q32.1. The ATXN3 gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated ATXN3 alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues); the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.
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脊髓小脑共济失调3型发病机制的新概念及综合治疗策略
脊髓小脑共济失调3型(SCA3),也称为Machado-Joseph病(MJD),是一种常染色体显性神经退行性疾病,主要累及小脑、锥体、锥体外系、运动神经元和动眼肌系统。SCA3具有很强的表型异质性,其SCA3的致病突变包括ATXN3基因外显子10 CAG通道的扩增,位于14q32.1。ATXN3基因在神经元和非神经元组织中普遍表达,并参与细胞蛋白质量控制途径。突变的ATXN3等位基因存在约45至87CAG重复序列,导致ataxin-3中聚谷氨酰胺束扩大。突变后,多q通道达到病理阈值(约50个谷氨酰胺残基);该蛋白被认为可能通过一些不清楚的机制获得神经毒性功能。我们对脊髓小脑性共济失调3型的发病机制和治疗策略进行了综述。扩增蛋白的转化可以通过增强蛋白的再折叠和降解或阻止蛋白水解裂解来实现,并通过改变蛋白在细胞核和细胞质之间的转运能力来阻止蛋白到达毒性位点。蛋白酶体降解和增强自噬聚集体清除是目前提出的显著治疗方法。尽管进行了广泛的研究,但由ataxin-3突变引起的细胞毒性的分子机制目前仍然没有预防性的治疗方法。这些治疗策略可能能够改善SCA3的体征症状,并减缓疾病进展。
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